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Table 1 A Summary of Molecule Target Therapies in HCC

From: Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities

Molecule Target cell Therapeutic setting Major effects Reference
CCR2 TAMs CCR2 antagonist Inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs [34]
CCR2 TAMs Anti-CCR2 Promotes epithelial‑to‑mesenchymal transition by upregulating matrix metalloproteinase‑2 [35]
CCR2 TAMs CCR2 monoclonal antibody Inhibits recruitment of monocytes [36]
CSF-1 TAMs CSF-1 receptor antagonist Reprograms polarization of TAMs [37]
IL-6 TAMs Anti-IL-6 Blocks downstream effect of TAM products [38]
IL-6 MDSCs Anti-IL-6 IL-6 expression levels strongly correlate with an MDSC phenotype and chemotherapy response in HCC patients [44]
chemokine (C-C motif) ligand 26 MDSCs Blockade of chemokine (C-C motif) ligand 26 Knockdown of chemokine (C-C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth [45]
SSAO MDSCs SSAO inhibitors May have an anti-tumor effect on HCC by inhibiting recruitment of CD11b+ and Gr-1+ cells and hindering angiogenesis [46]
STAT3 MDSCs Anti-STAT3 Inhibiting STAT3 can enhance the clinical efficacy of CAR-T cells in LM through modulation of L-MDSC [47]
CCRK MDSCs Anti-CCRK Hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G-csf expression to enhance polymorphonuclear MDSCs recruitment and tumorigenicity in HCC [48]
CCL9/CCR1 MDSCs Blockade of CCL9/CCR1 CCL9 secreted by splenic macrophages induces a CCR1‑dependent accumulation of MDSCs in the spleen in a murine H22 hepatoma model [49]
ENTPD2/CD39L1 MDSCs Blockade of ENTPD2/CD39L1 Hypoxia induces the expression of ENTPD2 on cancer cells leading to elevated extracellular 5'-AMP, which promotes the maintenance of MDSCs by preventing their differentiation in HCC [50]
PD-L1 MDSCs PD-1 monoclonal antibody PD-L1+ MDSCs could be used as a new biomarker of HCC [51]
 IL-18/TLR2 MDSCs Blockade of IL-18/TLR2 IL-18 administration was sufficient to induce accumulation of MDSC, whereas hepatocyte-specific silencing of IL-18 in TLR2(-/-) mice decreased the proportion of MDSC [52]
TGF-β/Axl/CXCL5 TANs Blockade of TGF-β/Axl/CXCL5 The synergy of TGF-β and Axl induces CXCL5 secretion, causing the infiltration of neutrophils into HCC tissue. [72]
cortisol TANs Inhibition of cortisol increased cortisol production and TAN/TAM infiltration as primary factors in the gender disparity of HCC development in both fish and human [73]
 CXCR2/CXCL1 TANs Blockade of CXCR2/CXCL1 The CXCR2-CXCL1 axis can regulate neutrophil infiltration into HCC tumor tissues and might represent a useful target for anti-HCC therapies [74]
CXCL17 TANs Anti-CXCL17 CXCL17 expression was associated with more CD68 and less CD4 cell infiltration [75]
CXCR6 TANs Anti-CXCR6 Human HCC samples expressing high levels of CXCR6 contained an increased number of CD66+ neutrophils and microvessels [76]
miRNA-21 CAFs MiRNA-21 inhibitor High level of serum exosomal miRNA-21 was correlated with greater activation of CAFs and higher vessel density in HCC patients [84]
CD24 CAFs Anti-CD24 HGF and IL6 secreted by CAFs promoted the stemness properties of CD24+ HCC cells through the phosphorylation of STAT3 [85]
LOXL2 CAFs Anti--LOXL2 The secreted LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation [86]
PD-L1/IL6/STAT3 CAFs Blockade of PD-L1/IL6/STAT3 HCC-CAFs regulate the survival, activation, and function of neutrophils within HCC through an IL6-STAT3-PDL1 signaling cascade [87]
IL6/STAT3 CAFs blockade of IL6/STAT3 IL-6 secreted by CAFs promotes stem cell-like properties in HCC cells by enhancing STAT3/Notch signaling [88]
Keratin 19 CAFs Anti-Keratin 19 Keratin 19 expression in HCC is regulated by Fibroblast-Derived HGF via a MET-ERK1/2-AP1 and SP1 Axis. [89]
LSD1 CAFs Anti-LSD1 LSD1 Stimulates Cancer-Associated Fibroblasts to Drive Notch3-Dependent Self-Renewal of Liver Cancer Stem-like Cells [90]
PD-1 Tregs PD-1 monoclonal antibody The ratio of CD4+CD127+ PD-1- T effector cells to CD4+Foxp3+PD-1+ Tregs was significantly increased following treatment with sorafenib [114]
PD-1 Tregs PD-1 monoclonal antibody Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity [115]
PD-1 Tregs PD-1 monoclonal antibody Sorafenib treatment enhanced functions of tumor-specific effector T cells as well as relieved PD-1-mediated intrinsic and Treg-mediated non-cell-autonomous inhibitions in tumor microenvironment [116]
CTLA4 Tregs CTLA4 monoclonal antibody Leptin inhibited Treg activation and function in vitro, demonstrated by lower expression of TGF-β, IL-10, CTLA4 and GITR in Tregs [117]
CTLA4 Tregs CTLA4 monoclonal antibody Tumor-induced regulatory DC subset suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production [118]
TIM3 Tregs TIM3 monoclonal antibody Antibodies against TIM3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects [119]
Lnc-Tim3 Tregs Anti-Lnc-Tim3 Lnc-Tim3 promotes T cell exhaustion, a phenotype which is correlated with compromised anti-tumor immunity [120]
TIM3 Tregs TIM3 monoclonal antibody TIM3 -1516 G/T polymorphisms may affect the prognosis of HBV-related HCC and may be new predictors of prognosis for HCC patients [121]
TIM3 Tregs TIM3 monoclonal antibody -1516G/T polymorphism in the promoter region of TIM3 gene may affect the disease susceptibility and HCC traits associated with HBV infection [122]
GITR Tregs GITR monoclonal antibody Agonistic targeting of GITR can enhance functionality of HCC TIL and may therefore be a promising strategy for single or combinatorial immunotherapy in HCC [123]
GITR Tregs GITR monoclonal antibody GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression in HCC. [124]
ICOS Tregs ICOS monoclonal antibody Regulatory T cells, especially ICOS+ FOXP3+ regulatory T cells, are increased in the HCCmicroenvironment and predict reduced survival [125]
OX40 Tregs OX40 monoclonal antibody OX40 expression in HCC is associated with a distinct immune microenvironment, specific mutation signature, and poor prognosis [126]
LAG3 Tregs LAG3 monoclonal antibody Antibodies against LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects [119]